Interactions between vascular smooth muscle cells (VSMC) and extracellular matrix (ECM) are important in the development and progression of many vascular diseases. The migration and invasion of dedifferentiation VSMC is a key event in this process. Normally quiescent, medial VSMC are stimulated to migrate and proliferate forming a hyperplastic neointima. They lose their contractile (quiescent) phenotype and respond to PDGF. We have investigated the relationship between VSMC differentiation and the motility, invasiveness, and interaction of these cells with ECM. VSMC from rat aorta readily proliferated on tissue culture plastic in response to serum. In contrast, VSMC cultured on reconstituted basement membrane (Matrigel) ceased proliferating and migrated to form networks of multicellular cord-like structures such as those seen in the aorta. We have demonstrated a strong ability of dedifferentiated VSMC to invade a Matrigel barrier in response to PDGF. In contrast, differentiated VSMC are 10-fold less invasive. We have noted roles for collagenase IV activity, TGF-beta, calcium, in vivo age, matrix metalloproteinase (MMP) activity is decreased to a reduction in 72 kD gelatinase mRNA accumulation, while in TGF-beta-treated VSMC, net activity is reduced through increased expression of the tissue inhibitors of matrix metalloproteinases (TIMPS). These observations suggest an important role and possible mechanisms for the interactions between VSMC and ECM in the development and progression of many vascular diseases.